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Comparing Nonlinear Pharmacokinetic Properties of
Therapeutic Drugs from 2000 to 2015
Giang Ho, Erik Gunderson, Adaeze Emecheta, Sarah BlackwellDr. Guohua An Team
Outline
◼ Background◼ Objective◼ Methods◼ Results◼ Conclusion◼ Limitations◼ Next Steps
Background
What is nonlinear pharmacokinetics?
◼ Nonlinear pharmacokinetics can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. [1]
Background
Causes of nonlinear PK [1]
◼ Reduced absorption◼ Protein binding saturation◼ Saturation of first pass metabolism ◼ Biotransformation saturation◼ Target-mediated drug disposition (TMDD)◼ Saturation of excretion
Background
Why did we choose to do this study? ◼ Nonlinear pharmacokinetic drugs pose a challenge
in therapy management due to their complex nature.
◼ Presently, there are no known databases dedicated to drugs of this class despite the growing number on the market.
Goal
Our goal is to improve medication management and patient care by analyzing the trends in the approval, use, mechanism of action, and formulation of nonlinear drugs.
Objective
◼ Using the FDA database, search for new drugs approved with nonlinear pharmacokinetic characteristics
◼ Analyze trends specific to this group of nonlinear drugs
Methods
◼ We chose which drugs to analyze for nonlinear pharmacokinetics by searching for new drug approvals on the FDA website from the years 2000-2015.
◼ We recorded the generic names, brand names, mechanism of action, metabolic pathway, dosing regimen, bioavailability and indications of all drugs approved in this time period.
Methods
The information on the package insert was used to determine which drugs exhibited nonlinear kinetics and the mechanism of the nonlinear kinetics◼ If the kinetics weren’t clear from the package
insert, we searched for additional resources in PubMed
Methods
Key words that can indicate a drug exhibits nonlinear pharmacokinetics -
◼ Nonlinear◼ Non-proportional/not proportional◼ Saturable ◼ Michaelis-Menten kinetics
Methods - Statistical Analysis
1. Student t-Test: Examine the comparison between the amount of linear vs. nonlinear drugs approved from 2000-2015
1. Fisher’s Exact Test: Comparison of drug classes between linear and nonlinear drugs approved from
2000-2015
Results
◼ From 2000-2015, the FDA approved 439 drugs in total◼ 96 (21%) are nonlinear drugs◼ 74 (77.1%) are small molecules, 22 (22.9%)
are large molecules/biologics
Results (cont)
0
5
10
15
20
25
30
35
40
45
50
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Nu
mb
er
Year
Number of linear and nonlinear drugs approved from 2000-2015
Non-linear drugs (N=94) Linear drugs (N=345)
p<0.0001
Results (cont)
0
5
10
15
20
25
30
35
40
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Pe
rce
nta
ge
(%
)
Year
Percentage of nonlinear drugs from 2000 to 2015
Results (cont)
0
2
4
6
8
10
12
14
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Num
ber
Year
Comparison of number of biologics and nonlinear biologics from 2000-2015
Number of Biologics Number of nonlinear Biologics
Absorption32%
Distribution7%
TMDD15%
Metabolism43%
Poor solubility3%
DISTRIBUTION OF NONLINEAR MECHANISM
anti-infectives15%
CNS agents13%
Electrolyte problems3%
Endocrines15%
Enzyme deficiencies4%
GI8%
Hypercholesterol3%
Hypertension2%
Immune suppressant5%
Macular degeneration2%
oncology26%
Others4%
DISTRIBUTION OF NONLINEAR DRUGS ACCORDING TO TREATMENT CLASSIFICATION
-1
1
3
5
7
9
11
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Num
ber
Year
Treatment classification of nonlinear drugs every year from 2000 to 2015
anti-infectives CNS agents Electrolyte problems Endocrines
Enzyme deficiencies GI Hypercholesterol Hypertension
Immune suppressant Macular degeneration oncology Others
Results (cont)
0 10 20 30 40 50 60 70 80
anti-infectives
CNS agents
Electrolyte problems
Endocrines
Enzyme deficiencies
GI
Hypercholesterol
Hypertension
Immune suppressant
Macular degeneration
oncology
Others
Total number
Comparison of nonlinear vs linear drug in treatment classification from 2000-2015
Linear drug Nonlinear drug
Results (cont)
Fisher’s Exact Test:
Odds ratio: (drugs oncologic-linear / drugs oncologic - nonlinear)(drugs non-oncologic-linear / drugs non-oncologic-non-linear)
Results (cont)Table 1. Treatment classification of nonlinear and linear drugs
Results (cont)
Conclusion:
It was determined that there were no significant differences on comparing the nonlinear vs. linear drugs in each class against the remaining total, hence accepting the null hypothesis (p<0.0024, CI=95%).
Results (cont)
◼ Nonlinear drug is a component of therapeutic monitoring
◼ Only 13 out of 96 drugs actually made into guideline▪ 2 out of 14 are biologics
Results (cont)
Clinical guideline(s) examined Nonlinear drugs listed for TDM Type of nonlinear drugs
Gao et al[9] Erlotinib, Gefitinib, Sunitinib, Nilotinib,
Sorafenib
Oncology (N=5)
Medina et al[10] Tocilizumab Immune suppressant (N=1)
Heimke et al[11] Rivastigmine, Paroxetine, Iloperidone,
Lamotrigine, Fluvoxamine
CNS agent (N=5)
Casteele et al[12] Natalizumab, Temsirolimus Immune suppressant (N=2)
Table 2. List of nonlinear drugs mentioned in clinical TDM guidelines.
Conclusion
◼ On average, one in five approved drugs have nonlinear pharmacokinetic properties
◼ Nonlinear pharmacokinetics are independent from molecular weight, treatment classification, and other drug properties
◼ Most nonlinear mechanisms come from changes in metabolism and absorption▪ A significant portion of nonlinear drugs exhibit
TMDD
Conclusion
◼ Very few nonlinear drugs have specific guidelines or clinical monitoring instructions ▪ Some of these drugs patients may use on an “as
needed” basis at home, increasing the risk of sub- or supra-therapeutic levels
→ There is a need to include monitoring guides for these drugs for patients to take home
Limitations
◼ Database isn’t complete - only 15 years have been analyzed, there could be additional or extended trends we didn’t see
◼ Drug classes were based on indication◼ Drugs with multiple uses were only placed
into one category
Next Steps
◼ Continue to search for nonlinear drugs as new drugs are approved, and search through drugs approved before 2000 to complete the database
◼ Optimize the complete database for use in the clinical/acute setting to improve drug monitoring and patient management
References
Bauer LA. Chapter 8. Clinical Pharmacokinetics and Pharmacodynamics. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds.Pharmacotherapy: A Pathophysiologic Approach, 8e. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/content.aspx?bookid=462&Sectionid=41100774. Accessed December 08, 2016.
Drugs@FDA: FDA Approved Drug Products. Retrieved from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
Gao B, Yeap S, Clements A, Balakrishnar B, Wong M, Gurney H. Evidence for therapeutic drug monitoring of targeted anticancer therapies. J Clin Oncol. 2012 Nov 10;30(32):4017-25. doi: 10.1200/JCO.2012.43.5362. Epub 2012 Aug 27. Review.PubMed PMID: 22927532.
References contd.
Medina F, Plasencia C, Goupille P, Ternant D, Balsa A, Mulleman D. Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Rheumatoid Arthritis. Ther Drug Monit. 2017 Aug;39(4):364-369. Doi: 10.1097/FTD.0000000000000421. PubMed PMID: 28700520.
Kempf E, Bogaerts J, Lacombe D, Liu L. 'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research. Eur J Cancer. 2017 Oct 4;86:143-149. Doi: 10.1016/j.ejca.2017.08.028. [Epub ahead of print] PubMed PMID: 28987771.
Ludden, T.M. Nonlinear Pharmacokinetics. Clin. Pharmacokinet. (1991) 20: 429. https://doi.org/10.2165/00003088-199120060-00001
Comparing Nonlinear Pharmacokinetic Properties of
Therapeutic Drugs from 2000 to 2015
Giang Ho, Erik Gunderson, Adaeze Emecheta, Sarah Blackwell, Dr. Guohua An
